To study the possible involvement of (met5)-enkephalin (ME) in psychiatric disorders, we studied the effects of antipsychotic drugs and electroconvulsive shock (ECS) on ME content in various rat brain regions. Chronic treatment with haloperidol not only increases the ME content in striatum and N. accumbens but also elevates the content of ME-like peptide which may function as the precursor of ME. The effect of haloperidol on ME system may be mediated through the cholinergic neurons in striatum since scopolamine reduced greatly haloperidol-induced increase in ME content. This notion is further supported by the finding that chronic administration of DFP increases striatal ME content. Repeated ECS cause an increase in ME content in hypothalamus and some limbic areas such as N. accumbens, septum and amygdala. The temporal characteristics of this increase resembles the time course of the clinical effects of ECS suggesting the possibility that the ME increase may participate in the antidepressive action of ECS. Finally it was demonstrated that prolonged recurrent seizures may cause a selective increase in the production of hippocampal ME.